N-(2-oxo-1-phenylpiperidin-3-yl)sulfonamides for the identification of biological and pharmacological activity

ABSTRACT

Novel compounds are continually sought after to treat and prevent diseases and disorders. The invention relates to N-(2-oxo-1-phenylpiperidin-3-yl)sulfonamides useful for being biologically and pharmacologically screened, and to contribute to the exploration and identification of new lead molecules that are capable of modulating the functional activity of a biological target.

This application claims priority under 35 U.S.C. 365(c) fromPCT/IB2010/052856, filed 23 Jun. 2010, the disclosure of which isincorporated by reference herein.

FIELD OF THE INVENTION

The field of the invention is medicinal chemistry. The invention relatesto N-(2-oxo-1-phenylpiperidin-3-yl)sulfonamides useful for theidentification of biological and pharmacological activity in drugdiscovery.

BACKGROUND OF THE INVENTION

Novel compounds are continually sought after to treat and preventdiseases and disorders. Pharmaceutical companies interested in owningnew active molecules develop or purchase chemical compounds or librariesin order to screen their activity against a particular target, aiming atthe identification of new industrially useful products.

Therefore, there is a market of customer companies for which theacquisition of novel chemical compounds, not already biologicallyexplored, is a key issue. And for the companies whose core business isthe design and preparation of chemical compounds or chemical libraries,their commercialization has a clear industrial interest.

Although many research groups work to find novel compounds to be used inthe treatment of known or novel diseases, the number of active newchemical entities in the market doesn't grow in the same extension. Overthe past few years, there has been a progressive reduction in the numberof medicines entering the market mainly due to the more stringentregulatory requirements that have raised the bar on safety and efficacyof new drugs.

The compounds described in this invention are useful for contributing tothe exploration of the chemical space, for incrementing the structuraldiversity of valuable molecules in the pharmaceutical sector and forincrementing the elements of structural recognition in order to studytheir interaction with or modulation of targets of pharmaceutical ormedicinal chemistry interest. For instance, the molecules may betherapeutically useful as anti-inflammatory or anticoagulation agents,among many other applications.

Compounds described in this invention are useful for being biologicallyand pharmaceutically explored, and therefore to contribute in theresearch and identification of new drug leads exhibiting the ability oftarget modulation, since these molecules are sources of chemicaldiversity not currently explored. The compounds of the present inventionmay be explored by means of any known method of biological screening.These methods comprise, but are not limited to, receptor affinityassays, ELISA assays, “southern”, “western” and “northern blot”, andcompetitive binding assays.

U.S. Pat. No. 7,126,006 B2 (The Scripps Research Institute) describesglycoluryl type molecules as scaffolds in the preparation ofcombinatorial libraries.

U.S. Pat. No. 6,939,973 B1 (The Scripps Research Institute) describesglycoluryl type molecules as scaffolds in the preparation ofcombinatorial libraries.

Smallheer et al. (Bioorganic & Medicinal Chemistry Letters (2008),18(7), 2428-2433) disclose a series of sulfonamidolactams useful ascoagulation Factor Xa inhibitors.

WO2004041776 (Bristol-Myers Squibb Company) discloses certainsulfonylamino-valerolactams that can be used as inhibitors oftrypsin-like serine proteases, specifically factor Xa.

WO2002102380 (Bristol-Myers Squibb Pharma. Co.) discloses monocyclic andbicyclic carbocycles and heterocycles active as factor Xa inhibitors.

The search for novel drug lead compounds for drug discovery is adifficult task that has traditionally required the use of hundreds ofthousands of compounds to reach a successful molecule, mainly due to thefact that drug discovery was driven by random screening and the chemicaland biological intuition.

However, integrated approaches combining structural knowledge fromconformationally constrained small peptides and parallel synthesis ofsmall molecules are particularly well suited for the shortening of thetime-consuming drug discovery process.

Compounds of formula (I) have been designed using computationaltechniques such as virtual library screening based on pharmacophoresearch. Virtual (database) screening (VS) is an important component ofthe computer-based search of novel lead compounds. The primary VSpremise is to screen a database of molecules computationally usingstructural descriptors that relate in some way to potential biologicalactivity. A subset of database molecules found to match thesedescriptors can then be selected for subsequent biological analysis. Interms of novel lead discovery, pharmacophore searching is one of themost widely applied VS methods.

Compounds of formula (I) are not an arbitrary selection of a vast amountof molecules. On the contrary, they have been designed using as startingpoint a pharmacophore for at least BK antagonism. In this context, apharmacophore is defined as a critical arrangement of molecularfragments or features creating a necessary, although not sufficient,condition for biological activity and receptor affinity.

In order to improve the success of molecular bioactive conformations,applicants have defined the structure of compounds of formula (I) usinga pharmacophore based on Hoe 140, the most potent peptide antagonist ofbrakykinin (BK, sequence:D-Arg⁰-Arg¹-Pro²-Hyp³-Gly⁴-Thi⁵-Ser⁶-D-Tic⁷-Oic⁸-Arg⁹ (Hyp,hydroxyproline; Thi, β-(2-thienyl)-alanine; Tic,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; Oic,(2S,3aS,7aS)-octahydroindole-2-carboxylic acid). The pharmacophore forBK antagonism has been obtained from a conformational search using aniterative simulated annealing procedure. Corcho, F J. ComputationalStudies on the Structure and Dynamics of Bioactive Peptides, PhD Thesis,2004.

In conclusion, all compounds of formula (I) exhibit at least Hoe 140pharmacophore fulfillment, and therefore they share specificcharacteristics for receptor affinity critical in the search of novelbioactive molecules.

DESCRIPTION OF THE INVENTION

The present invention concerns the compounds represented by formula (I)

and the salts and stereoisomers thereof, wherein

-   R¹ is hydrogen, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, and    polyhaloC₁₋₆alkoxy, aryl, Het;-   R² is C₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl;    C₁₋₆alkyl optionally substituted with C₃₋₇cycloalkyl, aryl or Het;    C₂₋₆alkenyl optionally substituted with C₃₋₇cycloalkyl, aryl or Het;    aryl; Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each    independently, C₁₋₆alkyl, or R^(4a) and R^(4b) together with the    nitrogen to which they are attached form a 5- or 6-membered    saturated heterocyclic ring;-   R³ is hydrogen, C₁₋₆alkylcarbonyl, C₁₋₆alkyl optionally substituted    with aryl, C₁₋₆alkoxyC₁₋₆alkyl, or C₃₋₇cycloalkyl, C₁₋₆alkyl    optionally substituted with Het;-   R⁴ is hydrogen, hydroxy, halo, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl,    C₁₋₆alkylcarbonyl, amino, mono- or diC₁₋₆alkylamino, azido,    mercapto, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy, C₁₋₆alkyl    optionally substituted with aryl or Het; C₃₋₇cycloalkyl optionally    substituted with C₁₋₆alkyl; C₁₋₆alkyl optionally substituted with    C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyl optionally substituted with    C₃₋₇cycloalkyl, aryl or Het; aryl; Het; or —NR^(4a)R^(4b), wherein    R^(4a) and R^(4b) are, each independently, C₁₋₆alkyl, or R^(4a) and    R^(4b) together with the nitrogen to which they are attached form a    5- or 6-membered saturated heterocyclic ring;-   n is one, two, three, four or five;-   p is one, two, three, four or five, independently of n;-   each aryl as a group or part of a group is phenyl or naphthalenyl,    each optionally substituted with one, two or three substituents    selected from halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, and    polyhaloC₁₋₆alkoxy;-   each Het as a group or part of a group is a monocyclic ring with 5    or 6 ring atoms or a bicyclic ring structure comprising a 6 membered    ring fused to a 4, 5, or 6 membered ring; each of the rings being    saturated, partially unsaturated, or completely unsaturated; at    least one of the rings containing 1 to 4 heteroatoms each    independently selected from nitrogen, oxygen and sulphur; and any    one of the rings being optionally substituted with one, two or three    substituents each independently selected from the group consisting    of halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆ alkoxy,    C₁₋₆ alkoxyC₁₋₆alkyl, C₁₋₆ alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.

The invention further relates to methods for the preparation of thecompounds of formula (I), the N-oxides, addition salts, quaternaryamines, metal complexes, and stereochemically isomeric forms thereof,their intermediates, and the use of the intermediates in the preparationof the compounds of formula (I).

The invention relates to the compounds of formula (I) per se, theN-oxides, addition salts, quaternary amines, metal complexes, andstereochemically isomeric forms thereof, for use as lead compounds to bebiologically and pharmacologically explored in the search andidentification of new drugs.

As used in the foregoing and hereinafter, the following definitionsapply unless otherwise noted.

The term halo is generic to fluoro, chloro, bromo and iodo.

The term “polyhaloC₁₋₆alkyl” as a group or part of a group, e.g. inpolyhaloC₁₋₆alkoxy, is defined as mono- or polyhalo substitutedC₁₋₆alkyl, in particular C₁₋₆alkyl substituted with up to one, two,three, four, five, six, or more halo atoms, such as methyl or ethyl withone or more fluoro atoms, for example, difluoromethyl, trifluoromethyl,trifluoroethyl. Preferred is trifluoromethyl. Also included areperfluoroC₁₋₆alkyl groups, which are C₁₋₆alkyl groups wherein allhydrogen atoms are replaced by fluorine atoms, e.g. pentafluoroethyl. Incase more than one halogen atom is attached to an alkyl group within thedefinition of polyhaloC₁₋₆alkyl, the halogen atoms may be the same ordifferent.

As used herein “C₁₋₄alkyl” as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 4 carbon atoms such as for example methyl, ethyl, 1-propyl, 2-propyl,1-butyl, 2-butyl, 2-methyl-1-propyl; “C₁₋₆alkyl” encompasses C₁₋₄alkylradicals and the higher homologues thereof having 5 or 6 carbon atomssuch as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl,2-methyl-1-butyl, 2-methyl-1-pentyl, 2-ethyl-1-butyl, 3-methyl-2-pentyl,and the like. Of interest amongst C₁₋₆alkyl is C₁₋₄alkyl.

The term “C₂₋₆alkenyl” as a group or part of a group defines straightand branched chained hydrocarbon radicals having saturated carbon-carbonbonds and one double bond, and having from 2 to 6 carbon atoms, such as,for example, ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl),1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl,3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl,2-methyl-2-pentenyl and the like. Of interest amongst C₂₋₆alkenyl isC₂₋₄alkenyl.

C₃₋₇cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

C₁₋₆alkoxy means C₁₋₆alkyloxy wherein C₁₋₆alkyl is as defined above.

It should be noted that the radical positions on any molecular moietyused in the definitions may be anywhere on such moiety as long as it ischemically stable.

Radicals used in the definitions of the variables include all possiblepositional isomers unless otherwise indicated. For instance pyridylincludes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl,2-pentyl and 3-pentyl.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

Whenever used hereinafter, the term “compounds of formula (I)”, or “thepresent compounds” or similar terms, it is meant to include thecompounds of formula (I), each and any of the subgroups thereof,N-oxides, addition salts, quaternary amines, metal complexes, andstereochemically isomeric forms.

The present disclosure also includes the prodrugs of compounds offormula (I).

One embodiment comprises the compounds of formula (I) or any subgroup ofcompounds of formula (I) specified herein, as well as the N-oxides,salts, as the possible stereoisomeric forms thereof. Another embodimentcomprises the compounds of formula (I) or any subgroup of compounds offormula (I) specified herein, as well as the salts as the possiblestereoisomeric forms thereof.

The compounds of formula (I) may have one or more centers of chiralityand may exist as stereochemically isomeric forms. The term“stereochemically isomeric forms” as used herein defines all thepossible compounds made up of the same atoms bonded by the same sequenceof bonds but having different three-dimensional structures which are notinterchangeable, which the compounds of formula (I) may possess.

With reference to the instances where (R) or (S) is used to designatethe absolute configuration of a chiral atom within a substituent, thedesignation is done taking into consideration the whole compound and notthe substituent in isolation.

Unless otherwise mentioned or indicated, the chemical designation of acompound encompasses the mixture of all possible stereochemicallyisomeric forms, which said compound may possess. Said mixture maycontain all diastereomers and/or enantiomers of the basic molecularstructure of said compound. All stereochemically isomeric forms of thecompounds of the present invention both in pure form or mixed with eachother are intended to be embraced within the scope of the presentinvention.

Pure stereoisomeric forms of the compounds and intermediates asmentioned herein are defined as isomers substantially free of otherenantiomeric or diastereomeric forms of the same basic molecularstructure of said compounds or intermediates. In particular, the term“stereoisomerically pure” concerns compounds or intermediates having astereoisomeric excess of at least 80% (i.e. minimum 90% of one isomerand maximum 10% of the other possible isomers) up to a stereoisomericexcess of 100% (i.e. 100% of one isomer and none of the other), more inparticular, compounds or intermediates having a stereoisomeric excess of90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms “enantiomerically pure” and“diastereomerically pure” should be understood in a similar way, butthen having regard to the enantiomeric excess, and the diastereomericexcess, respectively, of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of thisinvention may be obtained by the application of art-known procedures.For instance, enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids or bases. Examples thereof are tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid.Alternatively, enantiomers may be separated by chromatographictechniques using chiral stationary phases. Said pure stereochemicallyisomeric forms may also be derived from the corresponding purestereochemically isomeric forms of the appropriate starting materials,provided that the reaction occurs stereospecifically. Preferably, if aspecific stereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The diastereomeric racemates of the compounds of formula (I) can beobtained separately by conventional methods. Appropriate physicalseparation methods that may advantageously be employed are, for example,selective crystallization and chromatography, e.g. columnchromatography.

For some of the compounds of formula (I), their N-oxides, salts,solvates, quaternary amines, or metal complexes, and the intermediatesused in the preparation thereof, the absolute stereochemicalconfiguration was not experimentally determined. A person skilled in theart is able to determine the absolute configuration of such compoundsusing art-known methods such as, for example, X-ray diffraction.

The present invention is also intended to include all isotopes of atomsoccurring on the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

The term “prodrug” as used throughout this text means thepharmacologically acceptable derivatives such as esters, amides, andphosphates, such that the resulting in vivo biotransformation product ofthe derivative is the active drug as defined in the compounds of formula(I). The reference by Goodman and Gilman (The Pharmacological Basis ofTherapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, “Biotransformation ofDrugs”, p 13-15) describing prodrugs generally is hereby incorporated.Prodrugs preferably have excellent aqueous solubility, increasedbioavailability and are readily metabolized into the active inhibitorsin vivo. Prodrugs of a compound of the present invention may be preparedby modifying functional groups present in the compound in such a waythat the modifications are cleaved, either by routine manipulation or invivo, to the parent compound.

Preferred are pharmaceutically acceptable ester prodrugs that arehydrolysable in vivo and are derived from those compounds of formula (I)having a hydroxy or a carboxyl group. An in vivo hydrolysable ester isan ester, which is hydrolyzed in the human or animal body to produce theparent acid or alcohol. Suitable pharmaceutically acceptable esters forcarboxy include C₁₋₆alkoxymethyl esters for example methoxymethyl,C₁₋₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyl-oxyethylwhich may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counter-ion is pharmaceutically acceptable. However, saltsof acids and bases which are non-pharmaceutically acceptable may alsofind use, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) are able to form. The pharmaceutically acceptable acidaddition salts can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioicacid), tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

It will be appreciated that the compounds of formula (I) may have metalbinding, chelating, complex forming properties and therefore may existas metal complexes or metal chelates. Such metalated derivatives of thecompounds of formula (I) are intended to be included within the scope ofthe present invention.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

One embodiment of the present invention concerns compounds of formula(I) or of any subgroup of compounds of formula (I), wherein one or moreof the following conditions apply:

-   R¹ is hydrogen, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, and    polyhaloC₁₋₆alkoxy, aryl, Het;-   R² is C₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl;    C₁₋₆alkyl optionally substituted with C₃₋₇cycloalkyl, aryl or Het;    C₂₋₆alkenyl optionally substituted with C₃₋₇cycloalkyl, aryl or Het;    aryl; Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each    independently, C₁₋₆alkyl, or R^(4a) and R^(4b) together with the    nitrogen to which they are attached form a 5- or 6-membered    saturated heterocyclic ring;-   R³ is hydrogen, C₁₋₆alkylcarbonyl, C₁₋₆alkyl optionally substituted    with aryl, C₁₋₆alkoxyC₁₋₆alkyl, or C₃₋₇cycloalkyl, C₁₋₆alkyl    optionally substituted with Het;-   R⁴ is hydrogen;-   n is one, two, three, four or five;-   p is one;-   each aryl as a group or part of a group is phenyl or naphthalenyl,    each optionally substituted with one, two or three substituents    selected from halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, and    polyhaloC₁₋₆alkoxy;-   each Het as a group or part of a group is a monocyclic ring with 5    or 6 ring atoms or a bicyclic ring structure comprising a 6 membered    ring fused to a 4, 5, or 6 membered ring; each of the rings being    saturated, partially unsaturated, or completely unsaturated; at    least one of the rings containing 1 to 4 heteroatoms each    independently selected from nitrogen, oxygen and sulphur; and any    one of the rings being optionally substituted with one, two or three    substituents each independently selected from the group consisting    of halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.

Another embodiment of the present invention concerns compounds offormula (I) or of any subgroup of compounds of formula (I), wherein oneor more of the following conditions apply:

-   -   R¹ is hydrogen or C₁₋₆alkyl;    -   R² is C₁₋₆alkyl optionally substituted with C₃₋₇cycloalkyl, aryl        or Het; C₂₋₆alkenyl optionally substituted with C₃₋₇cycloalkyl,        aryl or Het; aryl; or Het;    -   R³ is hydrogen, C₁₋₆alkyl or carboxyl;    -   R⁴ is hydrogen;    -   n is one or two;    -   p is one;    -   each aryl as a group or part of a group is phenyl or        naphthalenyl, each optionally substituted with one, two or three        substituents selected from halo, hydroxy, nitro, cyano,        carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,        C₁₋₆alkylcarbonyl, amino, mono- or diC₁₋₆alkylamino, azido,        mercapto, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy;    -   each Het as a group or part of a group is a monocyclic ring with        5 or 6 ring atoms or a bicyclic ring structure comprising a 6        membered ring fused to a 4, 5, or 6 membered ring; each of the        rings being saturated, partially unsaturated, or completely        unsaturated; at least one of the rings containing 1 to 4        heteroatoms each independently selected from nitrogen, oxygen        and sulphur; and any one of the rings being optionally        substituted with one, two or three substituents each        independently selected from the group consisting of halo,        hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,        C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or        diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,        polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.

One embodiment of the present invention concerns compounds of formula(I) or of any subgroup of compounds of formula (I), wherein one or moreof the following conditions apply:

-   -   R¹ is hydrogen;    -   R² is C₂₋₆alkenyl optionally substituted with aryl or Het; aryl;        or Het;    -   R³ is hydrogen;    -   R⁴ is hydrogen;    -   n is one or two;    -   p is one;    -   each aryl as a group or part of a group is phenyl or        naphthalenyl, each optionally substituted with one or two        substituents selected from halo, amino, mono- or        diC₁₋₆alkylamino, and polyhaloC₁₋₆alkyl;    -   each Het as a group or part of a group is a monocyclic ring with        5 or 6 ring atoms or a bicyclic ring structure comprising a 6        membered ring fused to a 4, 5, or 6 membered ring; each of the        rings being saturated, partially unsaturated, or completely        unsaturated; at least one of the rings containing 1 to 4        heteroatoms each independently selected from nitrogen, oxygen        and sulphur; and any one of the rings being optionally        substituted with one or two substituents each independently        selected from the group consisting of halo and        polyhaloC₁₋₆alkyl.

The compounds of the present invention may be prepared according to theprocedures described hereinafter, which are meant to be applicable foras well the racemates, stereochemically pure intermediates or endproducts, or any stereoisomeric mixtures. The racemates orstereochemical mixtures may be separated into stereoisomeric forms atany stage of the synthesis procedures.

As shown in the above scheme 1, coupling of a compound of formula [4]with the primary amine compound of formula [5] gives the amidederivative compound of formula [6]. The coupling reaction occurs in anorganic solvent, such as a chlorinated solvent, preferablydichloromethane, 1,2-dichloroethane or chloroform, at a temperaturepreferably between −10° C. and 40° C., more preferably between 0° C. and25° C. Compound of formula [4] comprises a group —CO—R₇ in the form ofan activated carboxyl derivative, such as acid chlorides, anhydrides, oractive esters such as O-acylisoureas or acyloxyphosphonium derivatives.In a particular embodiment the carbonyl compound is carboxylic acid, thecarboxyl activate derivative is O-acylisourea and the activating groupis a carbodiimide coupling reagent such as dicyclohexylcarbodiimide(DCC), while in another the coupling group is diisopropylcarbodiimide(DIPC).

The corresponding reduction or deprotection reaction of compound [6]yields the alcohol of formula [7]. In a particular embodiment, R₆ groupis a benzyl protecting group, and the deprotection reaction comprisesthe chemoselective reduction of the metal hydride with a reductive agentsuch as NaBH₄ or Ca(BH₄)₂ in a polar protic solvent, such as ethanol or2-propanol at a temperature preferably between −10° C. and 25° C., morepreferably between 0° C. and 10° C.

The activation of compound [7] to furnish compound of formula [8] occursby means of sulfonyl halides, preferably para-toluenesulfonyl halides,methanesulfonyl halides or trifluoromethanesulfonyl halides, in thepresence of an organic aliphatic or aromatic base, such as pyridine,imidazole, or triethylamine. In a particular embodiment, R₈ group is amethanesulfonyl activating group, and the reaction occurs in achlorinated solvent, preferably dichloromethane, 1,2-dichloroethane orchloroform, in anhydrous or non anhydrous conditions, at a temperaturepreferably between −10° C. and 40° C., more preferably between 0° C. and25° C.

Treatment of compound [8] under cyclisation conditions yields the lactamcompound of formula [9] and the pyrrolidine compound of formula [10].The reaction occurs in the presence of an inorganic or organic base,such as sodium hydride, potassium tert-butoxide or lithiumdiisopropylamide, at a temperature preferably between −78° C. and 60°C., more preferably between −40° C. and 0° C. The reaction solvent is apolar aprotic solvent, preferably acetonitrile, tetrahydrofuran,dimethylformamide, or dimethylsulfoxide.

The N-deprotection of compounds [9] and [10] yields compounds offormulae [11] and [12], respectively where R₅ is an amino protectinggroup, carbamate, urea-type derivative, amide, cyclic imide, alkyl,aryl, imine, enamine or heteroatom. In a particular embodiment, theprotecting group is tert-butoxycarbonyl group and the deprotecting agentis trifluoroacetic acid in a chlorinated solvent, preferablydichloromethane, 1,2-dichloroethane or chloroform, at a trifluoroaceticacid composition preferably between 5% and 90%, more preferably between15% and 70%, at a temperature preferably between 0° C. and 45° C., morepreferably between 10° C. and 30° C.

The substitution reaction of [11] or [12] with compounds of formulaR₂—SO₂-LG, where LG means “leaving group”, being said LG grouppreferably an halogen atom, more preferably bromine or chlorine, yieldsthe corresponding substituted sulfonamides of formula [13] and [14],respectively. The reaction solvent is a chlorinated solvent, preferablydichloromethane, 1,2-dichloroethane or chloroform, or a polar aproticsolvent, preferably acetonitrile, tetrahydrofuran, or dimethylformamide,at a temperature preferably between 0° C. and 40° C., more preferablybetween 10° C. and 25° C.

Under substitution or coupling conditions with compounds of formulaR₃—Y, where Y means “leaving group” in substitution reaction and“activating group” in coupling reactions, being said Y preferably is ahalogen atom, more preferably bromine or chlorine in substitutionreaction, or an activated carboxyl derivative in coupling reactions,compounds [13] and [14] are converted to the final compounds of formula[1] and [2], respectively. The reaction solvent is a hydrous oranhydrous polar aprotic solvent, preferably acetonitrile,tetrahydrofuran, or dimethylformamide, at a temperature preferablybetween −78° C. and 60° C., more preferably between −78° C. and 25° C.

Both racemic as well as pure enantiomers of [1] and [2] can be accessedby this approach depending on the stereochemical integrity of thestarting material.

Alternatively, the compounds of formula [1] or [2] can be prepared bythe approach as shown in scheme 2. According to scheme 2, coupling of acompound of formula [4] with the compound of formula [5] gives the amidederivative compound of formula [6]. The coupling reaction occurs in anorganic solvent, such as a chlorinated solvent, preferablydichloromethane, 1,2-dichloroethane or chloroform, at a temperaturepreferably between −10° C. and 40° C., more preferably between 0° C. and25° C. Compound of formula [4] comprises a group —CO—R₇ in the form ofan activated carboxyl derivative, such as acid chlorides, anhydrides, oractive esters such as O-acylisoureas or acyloxyphosphonium derivatives.In a particular embodiment the carbonyl compound is carboxylic acid, thecarboxyl activate derivative is O-acylisourea and the activating groupis a carbodiimide coupling reagent such as dicyclohexylcarbodiimide(DCC), while in another the coupling group is diisopropylcarbodiimide(DIPC).

The N-deprotection of compound [6] yields compounds of formula [17]. Ina particular realization the protecting group is tert-butoxycarbonylgroup and the deprotecting agent is trifluoroacetic acid in achlorinated solvent, preferably dichloromethane, 1,2-dichloroethane orchloroform, at a trifluoroacetic acid composition preferably between 5%and 90%, more preferably between 15% and 70%, at a temperaturepreferably between 0° C. and 45° C., more preferably between 10° C. and30° C.

The coupling reaction of [17] with compounds of formula R₂—SO₂-LG, whereLG means “leaving group”, being said LG group preferably an halogenatom, more preferably bromine or chlorine, yields the correspondingsubstituted sulfonamide of formula [18]. The reaction solvent is achlorinated solvent, preferably dichloromethane, 1,2-dichloroethane orchloroform, or a polar aprotic solvent, preferably acetonitrile,tetrahydrofuran, or dimethylformamide, at a temperature preferablybetween 0° C. and 40° C., more preferably between 10° C. and 25° C.

The corresponding reduction or deprotection reaction of compound [18]yields the alcohol of formula [19]. In a particular embodiment, R₆ groupis a benzyl protecting group, and the deprotection reaction comprisesthe chemoselective reduction of the metal hydride with an reductiveagent such as NaBH₄ or Ca(BH₄)₂ in a polar protic solvent, such asethanol or 2-propanol at a temperature preferably between −10° C. and25° C., more preferably between 0° C. and 10° C.

Activation of compound [19] furnishes compound of formula [20]. Thereaction occurs by means of sulfonyl halides, preferablypara-toluenesulfonyl halides, methanesulfonyl halides ortrifluoromethanesulfonyl halides, in the presence of an organicaliphatic or aromatic base, such as pyridine, imidazole, ortriethylamine. The reaction occurs in a chlorinated solvent, preferablydichloromethane, 1,2-dichloroethane or chloroform, in anhydrous or nonanhydrous conditions, at a temperature preferably between −10° C. and40° C., more preferably between 0° C. and 25° C.

Treatment of compound [20] under cyclisation conditions yields thelactam compound of formula [13] and the pyrrolidine compound of formula[14]. The reaction occurs in the presence of an inorganic or organicbase, such as sodium hydride, potassium tert-butoxide or lithiumdiisopropylamide, at a temperature preferably between −78° C. and 60°C., more preferably between −40° C. and 0° C. The reaction solvent is apolar aprotic solvent, preferably acetonitrile, tetrahydrofuran,dimethylformamide, or dimethylsulfoxide.

Under substitution or coupling conditions with compounds of formulaR₃—Y, where Y means “leaving group” in substitution reaction and“activating group” in coupling reactions, being said Y preferably is ahalogen atom, more preferably bromine or chlorine in substitutionreaction, or an activated carboxyl derivative in coupling reactions,compounds [13] and [14] are converted to the final compounds of formula[1] and [2], respectively. The reaction solvent is a hydrous oranhydrous polar aprotic solvent, preferably acetonitrile,tetrahydrofuran, or dimethylformamide, at a temperature preferablybetween −78° C. and 60° C., more preferably between −78° C. and 25° C.Both racemic as well as pure enantiomers of [1] and [2] can be accessedby this approach depending on the stereochemical integrity of thestarting material.

The compounds of the present invention may be used, biologically andpharmacologically explored in the search and identification of new leadcompounds in the drug discovery process. The abovementioned usecomprises the compounds of formula (I)

and the salts and stereoisomers thereof, wherein

-   R¹ is hydrogen, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, and    polyhaloC₁₋₆alkoxy, aryl, Het;-   R² is C₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl;    C₁₋₆alkyl optionally substituted with C₃₋₇cycloalkyl, aryl or Het;    C₁₋₆alkenyl optionally substituted with C₃₋₇cycloalkyl, aryl or Het;    aryl; Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each    independently, C₁₋₆alkyl, or R^(4a) and R^(4b) together with the    nitrogen to which they are attached form a 5- or 6-membered    saturated heterocyclic ring;-   R³ is hydrogen, C₁₋₆alkylcarbonyl, C₁₋₆alkyl optionally substituted    with aryl, C₁₋₆alkoxyC₁₋₆alkyl, or C₃₋₇cycloalkyl, C₁₋₆alkyl    optionally substituted with Het;-   R⁴ is hydrogen, hydroxy, halo, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl,    C₁₋₆alkylcarbonyl, amino, mono- or diC₁₋₆alkylamino, azido,    mercapto, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy, C₁₋₆alkyl    optionally substituted with aryl or Het; C₃₋₇cycloalkyl optionally    substituted with C₁₋₆alkyl; C₁₋₆alkyl optionally substituted with    C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyl optionally substituted with    C₃₋₇cycloalkyl, aryl or Het; aryl; Het; or —NR^(4a)R^(4b), wherein    R^(4a) and R^(4b) are, each independently, C₁₋₆alkyl, or R^(4a) and    R^(4b) together with the nitrogen to which they are attached form a    5- or 6-membered saturated heterocyclic ring;-   n is one, two, three, four or five;-   p is one, two, three, four or five, independently of n;-   each aryl as a group or part of a group is phenyl or naphthalenyl,    each optionally substituted with one, two or three substituents    selected from halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, and    polyhaloC₁₋₆alkoxy;-   each Het as a group or part of a group is a monocyclic ring with 5    or 6 ring atoms or a bicyclic ring structure comprising a 6 membered    ring fused to a 4, 5, or 6 membered ring; each of the rings being    saturated, partially unsaturated, or completely unsaturated; at    least one of the rings containing 1 to 4 heteroatoms each    independently selected from nitrogen, oxygen and sulphur; and any    one of the rings being optionally substituted with one, two or three    substituents each independently selected from the group consisting    of halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.

The present invention comprises the use of the compounds of formula (I),their salts and stereoisomers used for being biologically andpharmacologically explored in the search and identification of new leadcompounds in the drug discovery process. The abovementioned usecomprises the compounds of formula (I)

and the salts and stereoisomers thereof, wherein

-   R¹ is hydrogen, halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, and    polyhaloC₁₋₆alkoxy, aryl, Het;-   R² is C₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl;    C₁₋₆alkyl optionally substituted with C₃₋₇cycloalkyl, aryl or Het;    C₂₋₆alkenyl optionally substituted with C₃₋₇cycloalkyl, aryl or Het;    aryl; Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each    independently, C₁₋₆alkyl, or R^(4a) and R^(4b) together with the    nitrogen to which they are attached form a 5- or 6-membered    saturated heterocyclic ring;-   R³ is hydrogen, C₁₋₆alkylcarbonyl, C₁₋₆alkyl optionally substituted    with aryl, C₁₋₆alkoxyC₁₋₆alkyl, or C₃₋₇cycloalkyl, C₁₋₆alkyl    optionally substituted with Het;-   R⁴ is hydrogen;-   n is one, two, three, four or five;-   p is one;-   each aryl as a group or part of a group is phenyl or naphthalenyl,    each optionally substituted with one, two or three substituents    selected from halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, and    polyhaloC₁₋₆alkoxy;-   each Het as a group or part of a group is a monocyclic ring with 5    or 6 ring atoms or a bicyclic ring structure comprising a 6 membered    ring fused to a 4, 5, or 6 membered ring; each of the rings being    saturated, partially unsaturated, or completely unsaturated; at    least one of the rings containing 1 to 4 heteroatoms each    independently selected from nitrogen, oxygen and sulphur; and any    one of the rings being optionally substituted with one, two or three    substituents each independently selected from the group consisting    of halo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- or    diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,    polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.

As such, in one embodiment, the present invention relates to a processfor preparing a compound of formula (I) as described herein, saidprocess comprising

a) reacting in a suitable medium compound of formula (II) with acompound of

andb) optionally further reacting in a suitable medium the product of stepa) with R₃—Y;whereinR₁, R₂, R₃, R₄, n and p have the same definition as provided herein;LG is a leaving group;Y is an activating group in coupling reactions or a leaving group insubstitution reactions.

The suitable medium of the reaction in step a) is anhydrous or nonanhydrous chlorinated solvent, preferably dichloromethane,1,2-dichloroethane or chloroform, or a hydrous or anhydrous polaraprotic solvent, preferably acetonitrile, tetrahydrofuran, ordimethylformamide, at a temperature preferably between 0° C. and 40° C.,more preferably between 0° C. and 25° C.

The suitable medium of the reaction in step b) is in the presence of aninorganic or organic base, such as sodium hydride, potassiumtert-butoxide or lithium diisopropylamide, at a temperature preferablybetween −78° C. and 60° C., more preferably between −78° C. and 25° C.The reaction solvent is a polar aprotic solvent, preferablyacetonitrile, tetrahydrofuran, dimethylformamide, or dimethylsulfoxide.

The term “leaving group” is preferably a halogen atom, more preferablybromine or chlorine.

The term “activating group” is preferably but not limited to a carboxylactivant in coupling reactions, preferably in the form of an acidchloride, anhydride, or active esters, such as O-acylisoureas oracyloxyphosphonium derivatives.

Compounds of formula (I) may be converted into each other followingart-known functional group transformation reactions. For example, aminogroups may be N-alkylated, nitro groups reduced to amino groups, a haloatom may be exchanged for another halo.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarbo-peroxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g., counter-current distribution,liquid chromatography and the like.

The compounds of formula (I) may be obtained as racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. The racemic compounds of formula (I), which aresufficiently basic or acidic may be converted into the correspondingdiastereomeric salt forms by reaction with a suitable chiral acid,respectively chiral base. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali oracid. An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography, in particularliquid chromatography using a chiral stationary phase. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound may be synthesized by stereospecific methods ofpreparation. These methods may advantageously employ enantiomericallypure starting materials.

One embodiment of the present invention concerns compounds of formula(IV) or any subgroup of compounds of formula (IV), and the salts andstereoisomers thereof, wherein one or more of the following conditionsapply

-   -   wherein    -   R¹ is hydrogen, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,        C₁₋₆alkoxy, C₁₋₆alkylcarbonyl, amino, mono- or diC₁₋₆alkylamino,        azido, mercapto, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy,        aryl, Het;    -   R⁴ is hydrogen, hydroxy, halo, nitro, cyano, carboxyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl,        C₁₋₆alkylcarbonyl, amino, mono- or diC₁₋₆alkylamino, azido,        mercapto, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy, C₁₋₆alkyl        optionally substituted with aryl or Het; C₃₋₇cycloalkyl        optionally substituted with C₁₋₆alkyl; C₁₋₆alkyl optionally        substituted with C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyl        optionally substituted with C₃₋₇cycloalkyl, aryl or Het; aryl;        Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each        independently, C₁₋₆alkyl, or R^(4a) and R^(4b) together with the        nitrogen to which they are attached form a 5- or 6-membered        saturated heterocyclic ring;    -   R₅ is an amino protecting group, in the form of carbamate,        urea-type derivative, amide, cyclic imide, alkyl, aryl, imine,        enamine or heteroatom;    -   n is one, two, three, four or five;    -   p is one, two, three, four or five, independently of n;

The invention further relates to compounds of formula (IV) per se, theN-oxides, addition salts, quaternary amines, metal complexes, andstereochemically isomeric forms thereof, for use as syntheticintermediates in the preparation of compounds of formula (I).

One embodiment of the present invention concerns compounds of formula(V) or any subgroup of compounds of formula (V), and the salts andstereoisomers thereof, wherein one or more of the following conditionsapply

-   -   wherein    -   R¹ is hydrogen, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,        C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino,        mono- or diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,        and polyhaloC₁₋₆alkoxy, aryl, Het;    -   R⁴ is hydrogen, hydroxy, halo, nitro, cyano, carboxyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl,        C₁₋₆alkylcarbonyl, amino, mono- or diC₁₋₆alkylamino, azido,        mercapto, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy, C₁₋₆alkyl        optionally substituted with aryl or Het; C₃₋₇cycloalkyl        optionally substituted with C₁₋₆alkyl; C₁₋₆alkyl optionally        substituted with C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyl        optionally substituted with C₃₋₇cycloalkyl, aryl or Het; aryl;        Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each        independently, C₁₋₆alkyl, or    -   R^(4a) and R^(4b) together with the nitrogen to which they are        attached form a 5- or 6-membered saturated heterocyclic ring;    -   R₅ is an amino protecting group, in the form of carbamate,        urea-type derivative, amide, cyclic imide, alkyl, aryl, imine,        enamine or heteroatom;    -   R₈ is an hydroxy activating group, preferably in the form of a        sulfonate ester, para-toluenesulfonyl, methanesulfonyl or        trifluoromethanesulfonyl;    -   n is one, two, three, four or five;    -   p is one, two, three, four or five, independently of n;

The invention further relates to compounds of formula (V) per se, theN-oxides, addition salts, quaternary amines, metal complexes, andstereochemically isomeric forms thereof, for use as syntheticintermediates in the preparation of compounds of formula (I).

One embodiment of the present invention concerns compounds of formula(VI) or any subgroup of compounds of formula (VI), and the salts andstereoisomers thereof, wherein one or more of the following conditionsapply:

-   -   wherein    -   R¹ is hydrogen, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl,        C₁₋₆alkoxy, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino,        mono- or diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,        and polyhaloC₁₋₆alkoxy, aryl, Het;    -   R⁴ is hydrogen, hydroxy, halo, nitro, cyano, carboxyl,        C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl,        C₁₋₆alkylcarbonyl, amino, mono- or diC₁₋₆alkylamino, azido,        mercapto, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy, C₁₋₆alkyl        optionally substituted with aryl or Het; C₃₋₇cycloalkyl        optionally substituted with C₁₋₆alkyl; C₁₋₆alkyl optionally        substituted with C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyl        optionally substituted with C₃₋₇cycloalkyl, aryl or Het; aryl;        Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each        independently, C₁₋₆alkyl, or R^(4a) and R^(4b) together with the        nitrogen to which they are attached form a 5- or 6-membered        saturated heterocyclic ring;    -   R₅ is an amino protecting group, carbamate, urea-type        derivative, amide, cyclic imide, alkyl, aryl, imine, enamine or        heteroatom;    -   n is one, two, three, four or five;    -   p is one, two, three, four or five, independently of n;

The invention further relates to compounds of formula (VI) per se, theN-oxides, addition salts, quaternary amines, metal complexes, andstereochemically isomeric forms thereof, for use as syntheticintermediates in the preparation of compounds of formula (I).

EXAMPLES

The following examples are intended to illustrate the present inventionand not to limit it thereto.

Example 1 Preparation of intermediate [6a]: Benzyl4-(tert-butoxycarbonyl-amino)-5-oxo-5-(phenylamino)pentanoate

To a stirred solution of Boc-L-glutamic acid 5-benzyl ester [4a] (41 g,122 mmol) in anhydrous CH₂Cl₂ (45 ml) at 0° C., was added during 15minutes a solution of DCC (30.1 g, 146 mmol) in anhydrous CH₂Cl₂ (45ml). The resulting white solid was sonicated. After that, anhydrousaniline was added dropwise to the reaction mixture over 10 minutes at 0°C. (11.1 ml, 122 mmol). The mixture was stirred at room temperature for40 minutes and filtered through Celite® to remove insoluble material.The resulting liquid was evaporated to dryness and chromatographicallypurified, yielding the desired product (47.2 g, 94%).

¹H-NMR (400 MHz, CDCl₃): δ: 8.40 (br, 1H, CONHPh), 7.43 (d, 2H, J=7.7Hz, 2H_(a)), 7.28 (d, 2H, J=7.7 Hz, H_(b)), 7.20 (m, 5H, 5×H_(d)), 7.02(t, 1H, J=7.4 Hz, H_(c)), 5.35 (d, 1H, J=7.8 Hz, CHNHBoc), 5.04 (d, 2H,J=2.6 Hz, BnOCH ₂), 4.26 (sa, 1H, CH₂CHNHBoc), 2.60-2.52 (mc, 1H,1×OCOCH ₂CH₂), 2.46-2.38 (mc, 1H, 1×OCOCH ₂CH₂), 2.21-2.12 (mc, 1H,1×OCOCH ₂CH₂), 1.99-1.90 (mc, 1H, 1×OCOCH₂CH ₂), 1.40 (s, 9H, NHCO₂C(CH₃)₃) ppm.

MS: Positive mode [M+Na]⁺=435.

MS: Negative mode [M+2H₂O−H]⁻=447.

CAS nr: [126349-57-3]

Example 2 Preparation of intermediate [7a]: Tert-butyl5-hydroxy-1-oxo-(phenylamino)pentan-2-ylcarbamate

To a stirred suspension of NaBH₄ (12.5 g, 342 mmol) in 200 ml EtOH at 0°C. was added crushed CaCl₂ (19.9 g, 171 mmol) in portions during 15 min.After that, compound [6a] (35.2 g, 85.8 mmol) was added in portionsduring 10 minutes. The solution was stirred for 3.5 h, warming to roomtemperature. The crude was neutralized at 0° C. using HCl 0.1 M, and theaqueous phase was extracted in AcOEt. The organic phase was washed usingsaturated NaCl, dried over anhydrous Na₂SO₄ and evaporated to dryness.The resulting oil residue was chromatographically purified over SiO₂ inHexane/AcOEt (40:60), furnishing the desired product (17.4 g, 65%).

¹H-NMR (300 MHz, CDCl₃), δ: 8.85 (br, 1H, CONHPh), 7.50 (dd, 2H, J₁=8.7Hz, J₂=1.2 Hz, 2×H_(a)), 7.27 (dd, 2H, J₁=8.4 Hz, J₂=7.8 Hz, 2×H_(b)),7.08 (t, 1H, J_(r)=7.2 Hz, H_(c)), 5.57 (sa, 1H, J=5.7 Hz, CHNHBoc),4.41 (br, 111, J=5.7 Hz, CHNHBoc), 3.74 (m, 2H, CH₂OH), 2.94 (br, 1H,CH₂OH), 2.0-1.65 (mc, 4H, CH₂CH₂), 1.44 (s, 9H, NHCO₂C(CH₃)₃) ppm.

¹³C-NMR (75 MHz, CDCl₃), δ: 170.6 (CONHPh), 156.2 (C(CH₃)₃), 137.7(NHCO₂), 128.9 (C_(Ar)—H_(b)), 124.3 (C_(Ar)—H_(c)), 119.9(C_(Ar)—H_(a)), 62.4 (CH₂OH), 54.6 (CHNHBoc), 30.1 (CH₂ CH₂), 28.3(NHCO₂C(CH₃)₃), 28.0 (CH₂CH₂) ppm.

MS: Positive mode [M+H]⁺=309, [M+Na]⁺=331.

MS: Negative mode [M−H]⁻=307.

Example 3 Preparation of intermediate [8a]:4-(tert-butoxycarbonylamino)-5-oxo-(phenylamino)pentyl methanesulfonate

To a stirred solution of compound [7a] (0.98 g, 3.19 mmol) in 10 mlanhydrous CH₂Cl₂ was added 0.66 ml of anhydrous Et₃N (4.76 mmol, 1.48eq) at 0° C. To this solution was added MsCl (3.86 mmol, 1.21 eq) andthe mixture was stirred for 2 h at 0° C. After then, the crude wasevaporated to dryness, and filtered over SiO₂ using AcOEt as the eluant.Once the filtered was evaporated, finally it was crystallized in acetoneat 0° C., yielding 1.12 g (91%) of the desired product.

¹H-NMR (300 MHz, CDCl₃): δ 8.435 (s, 1H), 7.512 (dd, J₁=7.8 Hz, J₂=8.4Hz, 2H), 7.293 (t, J=8.4 Hz, 2H), 7.091 (t, J=7.5 Hz, 1H), 5.375 (d,J=8.4 Hz, 1H), 4.4 (m, 1H), 4.306 (m, 2H), 3.302 (s, 3H), 2.095-1.750(m, 4H), 1.446 (s, 9H) ppm.

¹³C-NMR (300 MHz, CDCl₃): δ 170.03, 156.15, 137.63, 128.93, 124.41,119.83, 69.18, 53.67, 37.46, 28.84, 28.28, 25.34 ppm.

MS: Positive mode [M+Na]⁺=409.

MS: Negative mode [M+2H₂O−H⁻]=421.

Example 4 Preparation of Intermediate [9a]:tert-butyl-2-oxo-1-phenylpiperidin-3-ylcarbamate

Under inert atmosphere, LDA (1.04 mmol, 2 eq) was added to a solution ofcompound [8a] (0.200 g, 0.52 mmol) in anhydrous THF (5 ml) at 0° C. Thesolution was stirred for 2.5 h, warming to room temperature. After then,the crude was evaporated to dryness, and purified over Al₂O₃ usingHexane/AcOEt from 70/30 to 50/50 as the eluant, yielding 0.09 g (60%) ofthe desired product [9a] and 0.60 g (40%) of the by-product [10a].

¹H-NMR (400 MHz, CDCl₃): δ 7.39 (t, J=7.6 Hz, 2H_(Ar)), 7.25 (m,3H_(Ar)), 5.5 (br, 1H, NHBoc), 4.26 (m, 1H, CHNHBoc), 3.71 (m, 2H,—CHCH₂CH₂CH ₂—), 2.61 (m, 1H, CHCH ₂CH₂CH₂—), 2.04 (m, 2H, —CHCH₂CH₂CH₂—), 1.71 (m, 1H, CHCH ₂CH₂CH₁₂—), 1.46 (s, 9H, ^(t)Bu) ppm.

¹³C-NMR (400 MHz, CDCl₃): δ 169.94 (CONH), 155.94 (OCONH), 142.47(C_(q), C_(Ar)), 129.15 (CH, C_(Ar)), 126.81 (CH, C_(Ar)), 125.64 (CH,C_(Ar)), 79.622 (C_(q), ^(t)Bu), 51.90 (—CHCH₂CH₂CH₂—), 50.14 (—CHCH₂CH₂CH₂—), 28.36 (CH₃, ^(t)Bu), 27.39 (—CHCH₂CH₂CH₂—), 21.14 ppm (—CHCH₂CH₂CH₂—).

MS: Positive mode [M+H]⁺=291, [M+Na]⁺=313.

Example 5 Preparation of Intermediate [10a]:Tert-butyl-2-(phenylcarbamoyl)-pyrrolidine-1-carboxylate

Under inert atmosphere, ^(t)BuOK (0.070 g, 0.65 mmol) was added to asolution of compound [8a] (0.250 g, 0.65 mmol) in anhydrous THF (5.8ml). The reaction mixture was heated up to 50° C. during 1 h. Afterthen, the crude was evaporated to dryness, and purified over SiO₂ usingHexane/AcOEt 50/50 as the eluant, yielding 0.183 g (97%) of the desiredproduct [10a].

¹H-NMR (300 MHz, CDCl₃): δ 9.5 (br, NHPhe), 7.51 (dd, J₁=8.9 Hz, J₂=1.2Hz, 2H_(Ar)), 7.31 (t, J=7.8 Hz, 2H_(Ar)), 7.08 (t, J=7.2 Hz, 1H_(Ar)),4.4 (br, 1H, CH), 3.4 (br, 2H, CH₂), 1.93 (m, 2H, CH₂), 1.49 (s, 9H,^(t)Bu), 1.49 (s, 2H, CH₂) ppm.

MS: Positive mode [M+H]⁺=291, [M+Na]⁺=313.

MS: Negative mode [M−H]⁻=289, [M+2H₂O−H]⁻=325.

Example 6 Preparation of Intermediate [11a]

To a stirred solution of [9a] (0.08 g, 0.28 mmol) in 1.5 ml of CH₂Cl₂was added 0.50 ml of trifluoroacetic acid at room temperature, and themixture was sealed and stirred for 0.5 h. After then, the crude wasevaporated to dryness, yielding an orange oily residue of the organicsalt [11a], which was precipitated using ^(i)Pr₂O. The remaining solidwas used without further purification.

Example 7 Preparation of Intermediate [12a]

To a stirred solution of [10a] (0.90 g, 3.11 mmol) in 13 ml of CH₂Cl₂was added 5.5 ml of trifluoroacetic acid at room temperature, and themixture was sealed and stirred for 1 h. After then, the crude wasevaporated to dryness, yielding an orange oily residue of the organicsalt [12a], which was used without further purification.

Example 8 Preparation ofN-(2-oxo-1-phenylpiperidin-3-yl)benzenesulfonamide

Under inert atmosphere, to a stirred solution of compound [12a] (0.093g, 0.29 mmol) in 1 ml anhydrous DMF at 0° C. was added anhydrous Et₃N(0.15 ml, 1.04 mmol). This mixture was stirred for 5 min, and thenPhSO₂Cl (0.06 ml, 0.44 mmol) was added at 0° C. The reaction was stirredfor 2 h at this temperature. Then, the solvent was removed and the crudewas chromatographically purified over SiO₂ using Hexane/AcOEt 50/50 asthe eluant, yielding 0.057 g (63%) of the desired product.

¹H-NMR (300 MHz, CDCl₃): δ 7.92 (dd, J₁=8.1 Hz, J₂=1.5 Hz, 2H_(Ar)),7.6-7.48 (m, 3H_(Ar)), 7.37 (dd, J₁=7.8 Hz, J₂=7.2 Hz, 2H_(Ar)), 7.26(ft, J_(r)=8.1 Hz, J₂=˜1 Hz, 1H_(Ar)), 7.16 (dd, J₁=8.1 Hz, J₂=1.5 Hz,1H_(Ar)), ˜6 (s, 1H, NHSO₂), 3.8-3.54 (mc, 3H, 1×CHCH₂CH₂CH₂—N+2×CHCH₂CH₂CH₂—N), 2.61 (m, 1H, —CHCH ₂CH₂CH₂—N), 2.1-1.8 (mc, 3H,1×CHCH₂CH₂CH₂—N+2×—CHCH₂CH ₂CH₂—N) ppm.

MS: Positive mode [M+H]⁺=331, [M+Na]⁺=353.

Example 9 Preparation ofN-(2-oxo-1-phenylpiperidin-3-yl)naphthalene-2-sulfonamide

Following a procedure analogous to that described in Example 8, thetitle compound was obtained as a white solid in 62% yield.

MS: Positive mode [M+H]⁺=380, [M+Na]⁺=403.

Example 10 Preparation ofN-(2-oxo-1-phenylpiperidin-3-yl)quinoline-8-sulfonamide

Following a procedure analogous to that described in Example 8, thetitle compound was obtained as a white solid in 63% yield.

MS: Positive mode [M+H]⁺=382, [M+Na]⁺=404.

Example 11 Preparation of4-Chloro-N-(2-oxo-1-phenylpiperidin-3-yl)benzene-sulfonamide

Following a procedure analogous to that described in Example 8, thetitle compound was obtained as grey oil in 90% yield.

MS: Positive mode [M+H]⁺=365, [M+Na]⁺=387.

Example 12 Preparation of5-(Dimethylamino)-N-(2-oxo-1-phenylpiperidin-3-yl)-naphthalene-1-sulfonamide

Following a procedure analogous to that described in Example 8, thetitle compound was obtained as yellow oil in 80% yield.

MS: Positive mode: [M+H]⁺=424, [M+Na]⁺=446.

Example 13 Preparation of5-Chloro-N-(2-oxo-1-phenylpiperidin-3-yl)thiophene-2-sulfonamide

Following a procedure analogous to that described in Example 8, thetitle compound was obtained as white oil in 80% yield.

MS: Positive mode [M+H]⁺=371, [M+Na]⁺=393.

Example 14 Preparation of(E)-N-(2-oxo-1-phenylpiperidin-3-yl)-2-phenylethene-sulfonamide

Following a procedure analogous to that described in Example 1, thetitle compound was obtained as a white solid in 71% yield.

MS: Positive mode [M+H]⁺=357, [M+Na]+=379.

Example 15 Preparation ofN-benzyl-N-(2-oxo-1-phenylpiperidin-3-yl)-benzenesulfonamide

Under inert atmosphere, to a stirred solution of NaH (2.5 mg, 0.05 mmol)in 0.10 ml anhydrous DMF at 0° C., was added a solution of compound ofExample 8 (0.02 g, 0.05 mmol) in 0.20 ml anhydrous DMF. After 1.5 h at0° C., benzyl bromide (7 μl, 0.05 mmol) was added to the reactionmixture. This mixture was stirred for 2 h, and then solvent wascompletely removed. The crude was chromatographically purified over SiO₂using Hexane/AcOEt 50/50 as the eluant, yielding 0.016 g (71%, purity92%) of the desired product.

¹H-NMR (300 MHz, CDCl₃): δ 7.92 (dd, J₁=8.1 Hz, J₂=1.5 Hz, 2H_(Ar)),7.6-7.48 (m, 3H_(Ar)), 7.37 (dd, J₁=7.8 Hz, J₂=7.2 Hz, 4H_(Ar)), 7.26(tt, J₁=8.1 Hz, J₂=˜1 Hz, 2H_(Ar)), 7.16 (dd, J₁=8.1 Hz, J₂=1.5 Hz,4H_(Ar)), 4.42 (sa, 2H, CH₂Ph), 3.8-3.54 (mc, 3H,1×CHCH₂CH₂CH₂—N+2×CHCH₂CH₂CH ₂—N), 2.61 (m, 1H, —CHCH ₂CH₂CH₂—N),2.1-1.8 (mc, 3H, 1×CHCH₂CH₂CH₂—N+2×—CHCH₂CH ₂CH₂—N) ppm.

Example 16 Preparation of benzyl4-(tert-butoxycarbonylamino)-5-oxo-5-(N-(2-oxo-1-phenylpiperidin-3-yl)phenylsulfonamido)pentanoate

Step 1: Under inert atmosphere, to a stirred solution of NaH (3 mg, 0.07mmol) in 0.10 ml anhydrous DMF at 0° C., was added a solution ofcompound of Example 8 (0.022 g, 0.06 mmol) in 0.20 ml anhydrous DMF. Thetemperature was maintained during 1.5 h.Step 2: Under inert atmosphere in another reaction vessel,N,N′-Diisopropyl carbodiimide (12 μl, 0.08 mmol) was added to a solutionof Boc-L-Glutamic acid-5-benzyl ester (0.022 g, 0.065 mmol) in 0.20 mlanhydrous DMF at room temperature. The temperature was maintained during1.5 h.Step 3: After 1.5 h, the reaction mixture of step 1 was added toreaction the reaction mixture of step 2 at room temperature, and wasstirred during 6 h. Then solvent was completely removed. The crude waschromatographically purified over Al₂O₃ using Hexane/AcOEt 25/75 as theeluant, yielding 0.025 g (60%, purity 93%) of the desired product.

¹H-NMR (300 MHz, CDCl₃): δ 7.92 (dd, J₁=8.1 Hz, J₂=1.5 Hz, 2H_(Ar)),7.6-7.48 (m, 3H_(Ar)), 7.37 (dd, J₁=7.8 Hz, J₂=7.2 Hz, 2H_(Ar)), 7.26(tt, J₁=8.1 Hz, J₂=˜1 Hz, 1H_(Ar)), ˜7.20 (mc, 7H, 7×H_(Ar)), 5.35 (d,1H, J=7.8 Hz, CHNHBoc), 5.04 (d, 2H, J=2.6 Hz, BnOCH ₂), 4.26 (sa, 1H,CH₂CHNHBoc), 3.8-3.54 (mc, 3H, 1×CHCH₂CH₂CH₂—N+2×CHCH₂CH₂CH ₂—N),2.2-1.8 (mc, 8H), 1.40 (s, 9H, NHCO₂C(CH ₃)₃) ppm.

1. A compound having formula (I)

and the salts and stereoisomers thereof, wherein R¹ is hydrogen, nitro,cyano, azido, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy; R² isC₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl; C₁₋₆alkyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; aryl; Het; or—NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each independently,C₁₋₆alkyl, or R^(4a) and R^(4b) together with the nitrogen to which theyare attached form a 5- or 6-membered saturated heterocyclic ring; R³ ishydrogen, C₁₋₆alkylcarbonyl, C₁₋₆alkyl optionally substituted with aryl,C₁₋₆alkoxyC₁₋₆alkyl, or C₃₋₇cycloalkyl, C₁₋₆alkyl optionally substitutedwith Het; R⁴ is hydrogen, hydroxy, halo, nitro, cyano, carboxyl,C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl,C₁₋₆alkylcarbonyl, amino, mono- or diC₁₋₆alkylamino, azido, mercapto,polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy, C₁₋₆alkyl optionallysubstituted with aryl or Het; C₃₋₇cycloalkyl optionally substituted withC₁₋₆alkyl; C₁₋₆alkyl optionally substituted with C₃₋₇cycloalkyl, aryl orHet; C₂₋₆alkenyl optionally substituted with C₃₋₇cycloalkyl, aryl orHet; aryl; Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, eachindependently, C₁₋₆alkyl, or R^(4a) and R^(4b) together with thenitrogen to which they are attached form a 5- or 6-membered saturatedheterocyclic ring; n is one, two, three, four or five; p is one, two,three, four or five, independently of n; each aryl as a group or part ofa group is phenyl or naphthalenyl, each optionally substituted with one,two or three substituents selected from halo, hydroxy, nitro, cyano,carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl,amino, mono- or diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,and polyhaloC₁₋₆alkoxy; and each Het as a group or part of a group is amonocyclic ring with 5 or 6 ring atoms or a bicyclic ring structurecomprising a 6 membered ring fused to a 4, 5, or 6 membered ring; eachof the rings being saturated, partially unsaturated, or completelyunsaturated; at least one of the rings containing 1 to 4 heteroatomseach independently selected from nitrogen, oxygen and sulphur; and anyone of the rings being optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- ordiC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.
 2. A compound according to claim1, wherein R¹ is hydrogen, nitro, cyano, azido, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy; R² is C₁₋₆alkyl optionally substituted withC₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyl optionally substituted withC₃₋₇cycloalkyl, aryl or Het; aryl; Het; or —NR^(4a)R^(4b), whereinR^(4a) and R^(4b) are, each independently, C₁₋₆alkyl, or R^(4a) andR^(4b) together with the nitrogen to which they are attached form a 5-or 6-membered saturated heterocyclic ring; R³ is hydrogen,C₁₋₆alkylcarbonyl, C₁₋₆alkyl optionally substituted with aryl,C₁₋₆alkoxyC₁₋₆alkyl, or C₃₋₇cycloalkyl, C₁₋₆alkyl optionally substitutedwith Het; R⁴ is hydrogen; n is one, two, three, four or five; p is one;each aryl as a group or part of a group is phenyl or naphthalenyl, eachoptionally substituted with one, two or three substituents selected fromhalo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- ordiC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy; and each Het as a group or part of a group is amonocyclic ring with 5 or 6 ring atoms or a bicyclic ring structurecomprising a 6 membered ring fused to a 4, 5, or 6 membered ring; eachof the rings being saturated, partially unsaturated, or completelyunsaturated; at least one of the rings containing 1 to 4 heteroatomseach independently selected from nitrogen, oxygen and sulphur; and anyone of the rings being optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- ordiC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.
 3. A compound according to claim 1, whereinR¹ is hydrogen; R² is C₁₋₆alkyl optionally substituted withC₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyl optionally substituted withC₃₋₇cycloalkyl, aryl or Het; aryl and Het; R³ is hydrogen, C₁₋₆alkyl andC₁₋₆alkylcarbonyl; R⁴ is hydrogen; n is one or two; p is one; each arylas a group or part of a group is phenyl or naphthalenyl, each optionallysubstituted with one, two or three substituents selected from halo,hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- ordiC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy; and each Het as a group or part of a group is amonocyclic ring with 5 or 6 ring atoms or a bicyclic ring structurecomprising a 6 membered ring fused to a 4, 5, or 6 membered ring; eachof the rings being saturated, partially unsaturated, or completelyunsaturated; at least one of the rings containing 1 to 4 heteroatomseach independently selected from nitrogen, oxygen and sulphur; and anyone of the rings being optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆ alkylcarbonyl, amino, mono- ordiC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.
 4. A compound according to anyone of claims 1-3, wherein R¹ is hydrogen; R² is C₂₋₆alkenyl optionallysubstituted with aryl or Het; aryl; or Het; R³ is hydrogen; R⁴ ishydrogen; n is one or two; p is one; each aryl as a group or part of agroup is phenyl or naphthalenyl, each optionally substituted with one ortwo substituents selected from halo, amino, mono- or diC₁₋₆alkylamino,and polyhaloC₁₋₆alkyl; and each Het as a group or part of a group is amonocyclic ring with 5 or 6 ring atoms or a bicyclic ring structurecomprising a 6 membered ring fused to a 4, 5, or 6 membered ring; eachof the rings being saturated, partially unsaturated, or completelyunsaturated; at least one of the rings containing 1 to 4 heteroatomseach independently selected from nitrogen, oxygen and sulphur; and anyone of the rings being optionally substituted with one or twosubstituents each independently selected from the group consisting ofhalo and polyhaloC₁₋₆alkyl.
 5. A method of using a compound havingformula (I) and the salts and stereoisomers thereof, for beingbiologically and pharmacologically explored in the search andidentification of new lead compounds in drug discovery

wherein R¹ is hydrogen, nitro, cyano, azido, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy; R² is C₃₋₇cycloalkyl optionally substituted withC₁₋₆alkyl; C₁₋₆alkyl optionally substituted with C₃₋₇cycloalkyl, aryl orHet; C₂₋₆alkenyl optionally substituted with C₃₋₇cycloalkyl, aryl orHet; aryl; Het; or —NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, eachindependently, C₁₋₆alkyl, or R^(4a) and R^(4b) together with thenitrogen to which they are attached form a 5- or 6-membered saturatedheterocyclic ring; R³ is hydrogen, C₁₋₆alkylcarbonyl, C₁₋₆alkyloptionally substituted with aryl, C₁₋₆alkoxyC₁₋₆alkyl, orC₃₋₇cycloalkyl, C₁₋₆alkyl optionally substituted with Het; R⁴ ishydrogen, hydroxy, halo, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl, C₁₋₆alkylcarbonyl, amino, mono-or diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy, C₁₋₆alkyl optionally substituted with aryl or Het;C₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl; C₁₋₆alkyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; aryl; Het; or—NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each independently,C₁₋₆alkyl, or R^(4a) and R^(4b) together with the nitrogen to which theyare attached form a 5- or 6-membered saturated heterocyclic ring; n isone, two, three, four or five; p is one, two, three, four or five,independently of n; each aryl as a group or part of a group is phenyl ornaphthalenyl, each optionally substituted with one, two or threesubstituents selected from halo, hydroxy, nitro, cyano, carboxyl,C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino,mono- or diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy; and each Het as a group or part of a group is amonocyclic ring with 5 or 6 ring atoms or a bicyclic ring structurecomprising a 6 membered ring fused to a 4, 5, or 6 membered ring; eachof the rings being saturated, partially unsaturated, or completelyunsaturated; at least one of the rings containing 1 to 4 heteroatomseach independently selected from nitrogen, oxygen and sulphur; and anyone of the rings being optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- ordiC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.
 6. A method of using thecompounds of formula (I), their salts and stereoisomers for beingbiologically and pharmacologically explored in the search andidentification of new lead compounds in the drug discovery process

and the salts and stereoisomers thereof, wherein R¹ is hydrogen, nitro,azido, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy; R² is C₃₋₇cycloalkyloptionally substituted with C₁₋₆alkyl; C₁₋₆alkyl optionally substitutedwith C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyl optionally substitutedwith C₃₋₇cycloalkyl, aryl or Het; aryl; Het; or —NR^(4a)R^(4b), whereinR^(4a) and R^(4b) are, each independently, C₁₋₆alkyl, or R^(4a) andR^(4b) together with the nitrogen to which they are attached form a 5-or 6-membered saturated heterocyclic ring; R³ is hydrogen,C₁₋₆alkylcarbonyl, C₁₋₆alkyl optionally substituted with aryl,C₁₋₆alkoxyC₁₋₆alkyl, or C₃₋₇cycloalkyl, C₁₋₆alkyl optionally substitutedwith Het; R⁴ is hydrogen; n is one, two, three, four or five; p is one;each aryl as a group or part of a group is phenyl or naphthalenyl, eachoptionally substituted with one, two or three substituents selected fromhalo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- ordiC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy; and each Het as a group or part of a group is amonocyclic ring with 5 or 6 ring atoms or a bicyclic ring structurecomprising a 6 membered ring fused to a 4, 5, or 6 membered ring; eachof the rings being saturated, partially unsaturated, or completelyunsaturated; at least one of the rings containing 1 to 4 heteroatomseach independently selected from nitrogen, oxygen and sulphur; and anyone of the rings being optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo, hydroxy, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkylcarbonyl, amino, mono- ordiC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl,polyhaloC₁₋₆alkoxy, and C₃₋₇cycloalkyl.
 7. A process for preparing acompound as claimed in claim 1, said process comprising the step of a)reacting in a suitable medium a compound of formula (II) with a compoundof formula (III)

and b) optionally further comprising the step of reacting in a suitablemedium the product of step a) with R₃—Y; wherein R₁, R₂, R₃, R₄, n and phave the same definition as provided in of claim 1; LG is an halogenatom; Y is an activating group in coupling reactions or a leaving groupin substitution reactions, wherein, in substitution reactions Y is anhalogen atom; wherein in coupling reactions Y is an activated carboxylderivative, or an active ester, wherein the suitable medium of thereaction in step a) is anhydrous or non anhydrous chlorinated solvent,or a hydrous or anhydrous polar aprotic solvent, at a temperaturebetween 0° C. and 40° C., wherein the suitable medium of the reaction instep b) is in the presence of an inorganic or organic base, at atemperature between −78° C. and 60° C., and wherein the reaction solventis a polar aprotic solvent.
 8. A compound having formula (IV)

and the salts and stereoisomers thereof, wherein R¹ is hydrogen, nitro,cyano, azido, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy; R⁴ is hydrogen,hydroxy, halo, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl, C₁₋₆alkylcarbonyl, amino, mono-or diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy, C₁₋₆alkyl optionally substituted with aryl or Het;C₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl; C₁₋₆alkyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; aryl; Het; or—NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each independently,C₁₋₆alkyl, or R^(4a) and R^(4b) together with the nitrogen to which theyare attached form a 5- or 6-membered saturated heterocyclic ring; R₅ iscarbamate, urea-type derivative, cyclic imide, alkyl, aryl, imine,enamine or heteroatom; n is one, two, three, four or five; and p is one,two, three, four or five, independently of n.
 9. A method of using thecompounds of formula (IV) as disclosed in claim 8 per se, the N-oxides,addition salts, quaternary amines, metal complexes, and stereochemicallyisomeric forms thereof, as synthetic intermediates in the preparation ofcorresponding compounds of formula (I).
 10. A compound having formula(V)

and the salts and stereoisomers thereof, wherein R¹ is hydrogen, nitro,cyano, azido, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy; R⁴ is hydrogen,hydroxy, halo, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl, C₁₋₆alkylcarbonyl, amino, mono-or diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy, C₁₋₆alkyl optionally substituted with aryl or Het;C₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl; C₁₋₆alkyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; aryl; Het; or—NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each independently,C₁₋₆alkyl, or R^(4a) and R^(4b) together with the nitrogen to which theyare attached form a 5- or 6-membered saturated heterocyclic ring; R₅ iscarbamate, urea-type derivative, cyclic imide, alkyl, aryl, imine,enamine or heteroatom; R₈ is a hydroxy activating group, n is one, two,three, four or five; and p is one, two, three, four or five,independently of n.
 11. A method of using the compounds of formula (V)as disclosed in claim 10 per se, the N-oxides, addition salts,quaternary amines, metal complexes, and stereochemically isomeric formsthereof, as synthetic intermediates in the preparation of correspondingcompounds of formula (I).
 12. A compound having formula (VI)

and the salts and stereoisomers thereof, wherein R¹ is hydrogen, nitro,cyano, azido, polyhaloC₁₋₆alkyl, and polyhaloC₁₋₆alkoxy; R⁴ is hydrogen,hydroxy, halo, nitro, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl or C₃₋₇cycloalkyl, C₁₋₆alkylcarbonyl, amino, mono-or diC₁₋₆alkylamino, azido, mercapto, polyhaloC₁₋₆alkyl, andpolyhaloC₁₋₆alkoxy, C₁₋₆alkyl optionally substituted with aryl or Het;C₃₋₇cycloalkyl optionally substituted with C₁₋₆alkyl; C₁₋₆alkyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; C₂₋₆alkenyloptionally substituted with C₃₋₇cycloalkyl, aryl or Het; aryl; Het; or—NR^(4a)R^(4b), wherein R^(4a) and R^(4b) are, each independently,C₁₋₆alkyl, or R^(4a) and R^(4b) together with the nitrogen to which theyare attached form a 5- or 6-membered saturated heterocyclic ring; R₅ iscarbamate, urea-type derivative, amide, cyclic imide, alkyl, aryl,imine, enamine or heteroatom; n is one, two, three, four or five; and pis one, two, three, four or five, independently of n.
 13. A method ofusing the compounds of formula (VI) as disclosed in claim 12 per se, theN-oxides, addition salts, quaternary amines, metal complexes, andstereochemically isomeric forms thereof, as synthetic intermediates inthe preparation of corresponding compounds of formula (I).